Better Understanding Why the Liver is a Highly Regenerative Organ
In adult mammals, the liver is the most regenerative organ, capable of significant regrowth following injury. Why is this the case? Researchers here point to a small subset of liver cells in mice that are distinguished by telomerase expression, and while mice and humans have quite different telomerase and telomere dynamics, indirect evidence suggests that a similar population may exist in our species. Significant telomerase expression is the characteristic of stem cells that allows for unlimited replication: telomerase acts lengthen telomeres, the caps at the ends of chromosomes that shorten with each cell division. When too short, cells enter senescence or destroy themselves. Lacking telomerase, the vast majority of cells can only divide a set number of times.
This segregation between a few privileged stem cells and the vast mass of restricted somatic cells is the primary strategy by which multicellular life keeps the incidence of cancer to a manageable level. Mutations occur constantly, and evolution requires mutation, even when harmful to individuals, but it is much harder for mutational damage to cause somatic cells to run amok, given their inherent limitations. Unsurprisingly then, researchers are interested in the source of the liver's regenerative capacity not just to improve on it, or to find ways to regenerate other organs, but also to gain insight into the origins and peculiarities of liver cancer.
A subset of liver cells with high levels of telomerase renews the organ during normal cell turnover and after injury, according to researchers. The cells are distributed throughout the liver's lobes, enabling it to quickly repair itself regardless of the location of the damage. Understanding the liver's remarkable capacity for repair and regeneration is a key step in understanding what happens when the organ ceases to function properly, such as in cases of cirrhosis or liver cancer. "It's critical to understand the cellular mechanism by which the liver renews itself. We've found that rare, proliferating cells are spread throughout the organ, and that they are necessary to enable the liver to replace damaged cells. We believe that it is also likely that these cells could give rise to liver cancers when their regulation goes awry."
The liver's cells, called hepatocytes, work to filter and remove toxins from the blood. The liver is unique among organs in its ability to fully regenerate from as little as 25 percent of its original mass. Stem cells and some cancer cells make enough telomerase to keep their telomeres from shortening. Mutations that block telomerase activity cause cirrhosis in mice and humans. Conversely, mutations that kick telomerase into high gear are frequently found in liver cancers. Telomerase is a protein complex that "tops off" the ends of chromosomes after DNA replication. Without its activity, protective chromosomal caps called telomeres would gradually shorten with each cell division. Most adult cells have little to no telomerase activity, and the progressive shortening of their telomeres serves as a kind of molecular clock that limits the cells' life span.
Researchers found that, in mice, about 3-5 percent of all liver cells express unusually high levels of telomerase. The cells, which also expressed lower levels of genes involved in normal cellular metabolism, were evenly distributed throughout the liver. During regular cell turnover or after the liver was damaged, these cells proliferate in place to make clumps of new liver cells. "These rare cells can be activated to divide and form clones throughout the liver. As mature hepatocytes die off, these clones replace the liver mass. But they are working in place; they are not being recruited away to other places in the liver. This may explain how the liver can quickly repair damage regardless of where it occurs in the organ. You could imagine developing drugs that protect these telomerase-expressing cells, or ways to use cell therapy approaches to renew livers. On the cancer side, I think that these cells are very strong candidates for cell of origin. We are finally beginning to understand how this organ works."
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What buffles me is why the evolution selected for such a great regenerative ability in an organ that is internal and should not accumulate that much damage before the age of 30-40. For example, the kidneys should be as important and should have the same capacity for regeneration. And cubes, eyes, and teeth are in immediate danger and quite important too. So the regenerative capacity might be a side effect of something else or a leftover of pre- mammalian ages...
@ Cuberat: since the liver is the first and ultimately last line of defense for filtering out toxins from the body, it can face adversity at any time. Thus, it makes sense that it's very regenerative if, say, a kid ingested some poison that killed a bunch of hepatocytes.
@DdR,
Hello DdR, depending on the poison or c be affecting kidneys too and they don't regenerate so well. Ironically some poison can damage the liver so badly that it will scar. In this case I wonder if liver resection would help to regenerate a here organ...
I agree with pretty much everything said, but there's a tone here that's implying that scarring is the end of the line. There is solid evidence for things like the bright streak of a recanalized hepatic artery on the ultrasound starting to break up and return to its normal aspect in cases of recovery without transplant. That is supported by histological examination of biopsies that show new growth breaking up scarred tissue. BUT...that's only been documented in cases of viral liver disease, not with Legere's cirrhosis (alcohol etiology). BUT...there are definitely cases that seem to fit that, and looking into the details, they're pretty much universally regarded as misdiagnoses, so prevalent is the belief that regeneration is impossible in those cases. I think this needs to be looked at in a more systematic controlled way. I think that there are routine violations of the model but by reclassifying them the discrepancy disappears. For eons we accepted that neural tissue does not regenerate, but now we know that if it gets cleared away there is a possibility of regeneration. That would mean the million dollar question is about the factors that encourage that pushing through scar tissue with new growth and why it's so much more likely in cases where the liver has not been damaged at a purely chemical contact level, like acetone, ether, chloroform, toluene, benzene, etc. compared to other etiologies. Which I mention because, as a statistician that has to look at control population variables vis a vis an experimental group, you really can't discriminate from liver disease caused by being vulnerable to it and drinking too much compared to not being vulnerable to it, making your own moonshine, and inadvertently drinking the heads on a regular basis. It presents the same. So, viral damage and chemical damage differentially affect whatever mechanism is driving regeneration in viral liver disease. But if it does happen and is just dismissed as an incorrect initial diagnosis, we all could really be missing a trick here. There is plenty of evidence that it does happen. Call me a philosophy student that had to get a real job, but I'm thinking we might need a paradigm change here in the way liver disease is conceptualized. That's not saying "everybody's wrong". The ancients followed the planets were intimately familiar with their movements, so were not ignorant of their "behavior", yet didn't even know they revolved around the sun. Point being, you can study a phenomenon and be convincingly familiar with it, and still not really grasp what is happening at all. I really think the liver and the immune system are the final frontiers. Medicine will advance so much if we can just bring those two areas in the fold, imho. OMGA- we know more about the brain than the liver and immune system! And we don't know squat about that. The importance of the gut biome could be added to that list, I guess. So, keep debating, throw out all kinds of contrary evidence, dispute loudly- that's how paradigms change. I'm more optimistic than Thomas Kuhn (who coined the term/concept). He thought they only changed when their proponents died. Quite possibly, but I'd like to think would could do better than than...occasionally?